SGLT2 inhibitor and loop diuretic induce different vasopressin and fluid homeostatic responses in non-diabetic rats

Loop diuretics are commonly used diuretics in the treatment of fluid retention, but induce hypovolemia-related renal dysfunction. Sodium-glucose cotransporter SGLT2 inhibitors induce osmotic diuresis but body fluid volume is maintained by stimulating vasopressin-induced fluid intake and collecting duct water reabsorption as reported in diabetic rats. We aimed to test the hypothesis that unlike SGLT2 inhibitors, loop diuretics lack activation of similar fluid homeostatic mechanisms. Non-diabetic male Sprague-Dawley rats were treated daily by oral gavage with vehicle, SGLT2 inhibitor ipragliflozin (5mg/kg) or loop diuretic furosemide (50mg/kg) and monitored in metabolic cages for 2 or 7 days. Ipragliflozin and furosemide similarly increased urine volume on day 2. This was associated with increased serum sodium concentration, urine vasopressin excretion, fluid intake, and solute-free water reabsorption in response to ipragliflozin but not to furosemide. Ipragliflozin maintained fluid balance (fluid intake - urine volume) on day 2 and total body water (TBW) measured by bioimpedance spectroscopy and serum creatinine on day 7. In comparison, furosemide decreased fluid balance on day 2, and decreased TBW and increased serum creatinine on day 7. Furosemide, but not ipragliflozin, increased plasma renin activity, and systolic blood pressure was similar among the groups. In conclusion, the osmotic diuresis of the SGLT2 inhibitor increased serum sodium concentration and the vasopressin-related stimulation of fluid intake and renal water retention maintained fluid balance, whereas the loop diuretic did not engage the compensatory vasopressin system. The data suggest differences in vasopressin and fluid homeostatic responses between SGLT2 inhibitors and loop diuretics.

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